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- EMDB-27896: The closed C0-state flycatcher TRPM8 structure in complex with PI... -

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Basic information

Entry
Database: EMDB / ID: EMD-27896
TitleThe closed C0-state flycatcher TRPM8 structure in complex with PI(4,5)P2
Map dataFull map, sharpened with B-factor -50
Sample
  • Complex: Transient receptor potential cation channel subfamily M member 8
    • Protein or peptide: Transient receptor potential cation channel subfamily M member 8
  • Ligand: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate
Function / homology
Function and homology information


detection of temperature stimulus / sensory perception of temperature stimulus / monoatomic cation transmembrane transport / monoatomic ion channel activity / membrane / identical protein binding
Similarity search - Function
Transient receptor potential cation channel subfamily M member 8 / TRPM, SLOG domain / SLOG in TRPM / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Biological speciesFicedula albicollis (Collared flycatcher)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.51 Å
AuthorsYin Y / Zhang F / Feng S / Butay KJ / Borgnia MJ / Im W / Lee S-Y
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Eye Institute (NIH/NEI)R01EY031698 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R35NS097241 United States
CitationJournal: Science / Year: 2022
Title: Activation mechanism of the mouse cold-sensing TRPM8 channel by cooling agonist and PIP.
Authors: Ying Yin / Feng Zhang / Shasha Feng / Kevin John Butay / Mario J Borgnia / Wonpil Im / Seok-Yong Lee /
Abstract: The transient receptor potential melastatin 8 (TRPM8) channel is the primary molecular transducer responsible for the cool sensation elicited by menthol and cold in mammals. TRPM8 activation is ...The transient receptor potential melastatin 8 (TRPM8) channel is the primary molecular transducer responsible for the cool sensation elicited by menthol and cold in mammals. TRPM8 activation is controlled by cooling compounds together with the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP). Our knowledge of cold sensation and the therapeutic potential of TRPM8 for neuroinflammatory diseases and pain will be enhanced by understanding the structural basis of cooling agonist- and PIP-dependent TRPM8 activation. We present cryo-electron microscopy structures of mouse TRPM8 in closed, intermediate, and open states along the ligand- and PIP-dependent gating pathway. Our results uncover two discrete agonist sites, state-dependent rearrangements in the gate positions, and a disordered-to-ordered transition of the gate-forming S6-elucidating the molecular basis of chemically induced cool sensation in mammals.
History
DepositionAug 18, 2022-
Header (metadata) releaseOct 26, 2022-
Map releaseOct 26, 2022-
UpdateOct 26, 2022-
Current statusOct 26, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

Downloads & links

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Map

FileDownload / File: emd_27896.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFull map, sharpened with B-factor -50
Voxel sizeX=Y=Z: 1.08 Å
Density
Contour LevelBy AUTHOR: 0.23
Minimum - Maximum-0.89168274 - 2.1425667
Average (Standard dev.)0.012006412 (±0.08726426)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 276.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_27896_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: Half map A

Fileemd_27896_half_map_1.map
AnnotationHalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: Half map B

Fileemd_27896_half_map_2.map
AnnotationHalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Sample components

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Entire : Transient receptor potential cation channel subfamily M member 8

EntireName: Transient receptor potential cation channel subfamily M member 8
Components
  • Complex: Transient receptor potential cation channel subfamily M member 8
    • Protein or peptide: Transient receptor potential cation channel subfamily M member 8
  • Ligand: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate

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Supramolecule #1: Transient receptor potential cation channel subfamily M member 8

SupramoleculeName: Transient receptor potential cation channel subfamily M member 8
type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Ficedula albicollis (Collared flycatcher)
Recombinant expressionOrganism: Homo sapiens (human)

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Macromolecule #1: Transient receptor potential cation channel subfamily M member 8

MacromoleculeName: Transient receptor potential cation channel subfamily M member 8
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Ficedula albicollis (Collared flycatcher)
Molecular weightTheoretical: 131.343406 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MATLFQVSMG SMRHRRNGNF ESSRLLYSSM SRSIDVACSD ADLANFIQEN FKKRECVFFT KDTKSMGNLC KCGYPENQHI EGTQVNTTE KWNYKKHTKE LPTDAFGDIQ FENLGKRGKY IRLSCDTDSE TLYDLMTQHW HLKTPNLVIS VTGGAKNFAL K PRMRKIFS ...String:
MATLFQVSMG SMRHRRNGNF ESSRLLYSSM SRSIDVACSD ADLANFIQEN FKKRECVFFT KDTKSMGNLC KCGYPENQHI EGTQVNTTE KWNYKKHTKE LPTDAFGDIQ FENLGKRGKY IRLSCDTDSE TLYDLMTQHW HLKTPNLVIS VTGGAKNFAL K PRMRKIFS RLIYIAQSKG AWIFTGGTHY GLMKYIGEVV RDNTISRSSE ENVVAIGIAA WGMISNRETL IRTADSDGSY LA HYIMDDL KRDPLYCLDN NHTHLLLVDN GTHGHPTIEA KVRTQLEKYI SERVIPESNY GGKIPIVCFA QGGGKETLKS INV AIKSKI PCVVVEGSGR IADVIASLVE AEGTLASSCV KESLLRFLPR TISRLSEEET ESWIKWIKEV LESPHLLTVI KIEE AGDEI VSNAISFALY KAFSTNEHDR DNWNGQLKLL LEWNQLDLAS DEIFTNDRNW ESADLQDVMF TALVKDRPKF VRLFL ENGL NLRKFLTTEV LRELYTNNFS SLVFKNLQIA KNSYNDALLT FVWKMVEDFR RGAKRDDKNS KDEMEIELSE ECPITR HPL QALFIWSVLQ NKKELSKVIW EQTRGCTLAA LGASKLLKSM AKVKNDINAA GESEELANEY ETRAVELFTE CYSNDED LA EQLLTYSCEA WGGSNCLELA VEARDQQFIA QPGVQNFLSK QWYGEISRDT KNWKIILCLF FFPLIGCGFI SFRKKPVE K TKKLFLYYVS FFTSPFVVFS WNVIFYIAFL LLFAYVLLMD FQKEPTALEI ILYVLVFILL CDEVRQWYMN GSKYFSDLW NVMDTLAIFY FIAGIVFRLH SDESSWYSGR VIFCLDYIVF TLRLIHIFTV SRNLGPKIIM LQRMMIDVFF FLFLFAVWMV AFGVARQGI LRKNEHRWEW IFRSVIYEPY LAMFGQYPDD IDGTTYNFDH CTFSGNESKP LCVELDANNQ PRFPEWITIP L VCIYMLST NILLVNLLVA MFGYTVGSVQ ENNDQVWKFQ RFFLVQEYCS RLTIPFPFVI FAYIFMVMRK CFKCCCKKES KE PSVCCSR NEDNEILAWE AVMKENYLVK INTKASDSSE EMVHRFRQLD AKLSDLKGLL KEISSKIKSN SLEVLFQGPD YKD DDDKAH HHHHHHHHH

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Macromolecule #2: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(o...

MacromoleculeName: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate
type: ligand / ID: 2 / Number of copies: 4 / Formula: PIO
Molecular weightTheoretical: 746.566 Da
Chemical component information

ChemComp-PIO:
[(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Support film - Film thickness: 2.0 nm / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.25 µm / Nominal magnification: 75000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Number real images: 4283 / Average electron dose: 42.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1308147
CTF correctionSoftware: (Name: Gctf, RELION)
Startup modelType of model: EMDB MAP
EMDB ID:

Details: The EM map for the previously reported apo TRPM8 structure (EMD-7127) was low-pass filtered to 30-Angstrom and used as an initial model without a reference mask.
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final angle assignmentType: PROJECTION MATCHING / Software - Name: cryoSPARC
Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.51 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 51879
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-8e4q:
The closed C0-state flycatcher TRPM8 structure in complex with PI(4,5)P2

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